摘要
慢性阻塞性肺疾病(COPD)患者对运动的脑卒中容量反应受损。本研究的目的是研究3个月的西地那非治疗是否改善了卒中量,如果是,这种改善是否与肺动脉压力有关,并转化为运动能力的改善。
共有15名稳定的COPD患者(慢性阻塞性肺疾病Ⅱ-Ⅳ全球倡议)在休息和运动时行右心脏导管插入术。行程体积通过磁共振成像(MRI)在休息和亚极量运动在仰卧位置的过程中评估,并与八个年龄匹配的对照组相比。此外,进行了心肺运动测试和6分钟步行距离测试。Ëxercise tests and MRI were repeated after 12 weeks of oral therapy with 50 mg sildenafil three times daily.
COPD患者的脑卒中量明显低于健康对照组(62±12)与81±22 mL at rest and 70±15与101±28 mL during exercise). Pulmonary hypertension (PH) was diagnosed in nine patients and was absent in six. Treatment with sildenafil had no effect on stroke volume or exercise capacity. Although the stroke volume was lower in COPD patients with associated PH in comparison with non-PH patients, there was no difference in treatment response between both groups.
在15周慢性阻塞性肺疾病的患者本组,减小的冲程体积在休息和运动过程中发现。Neither stroke volume nor exercise capacity were improved by 3 months of sildenafil therapy.
一些研究表明,慢性阻塞性肺疾病,每搏输出量(SV)(COPD)患者可能在休息可以减少和经常失败锻炼期间增加1-五。由于心输出量成比例地涉及组织氧气输送,受损SV响应(当不通过补偿增加心频率)可能有助于在COPD运动能力降低。
在运动过程中,右心室(RV)不能增加SV,部分原因被认为是由于肺血管扩张剂对增加的血流反应不足,导致右心室后负荷突然增加6,7。另一种解释是内在的右心功能不全,独立的后负荷。
西地那非已经被提出作为可能降低肺血管阻力(PVR)和提高右心室功能在COPD的药物。PVR减少通过增加一氧化氮(NO)的第二信使环GMP,从而导致钙敏感性钾离子通道的开口的细胞内水平发生。这导致细胞内钙离子水平的降低,这会导致血管舒张8。西地那非也可能增加冠状动脉灌注,这可能是肥厚RV重要,从而改善心脏功能9。此外,最近的一项研究表明,西地那非可使大鼠肥大的房车收缩力增加10。然而,这些结果还没有在人类中得到证实。因此,西地那非可改善双方降低RV后负荷和提高RV功能在COPD患者的心脏功能。如果西地那非与RV功能的改善有关,这可能会导致增加运动能力。这是最近由Holverda报道等。11在卧式自行车上进行次最大运动时的SV反应可以使用磁共振成像(MRI)进行非侵袭性评估。在本研究中,我们报道了口服西地那非治疗3个月对SV反应的影响,在最大运动能力下的测量,以及COPD合并和无肺动脉高压(PH)患者的运动能力。本报告的第一个目的是评估与对照组相比,COPD患者在休息或运动期间的SV是否较低。第二个目的是评估西地那非治疗对COPD组运动SV反应和运动能力的影响。最后,探讨肺动脉压力与治疗反应的关系。
材料与方法
主题
本研究共纳入稳定期COPD患者15例。根据全球慢性阻塞性肺病指南,纳入标准为中度至重度COPD12,and patients had to be without exacerbation or hospital admission in the previous 4 months. Exclusion criteria were a history of systemic hypertension, left-sided heart failure or pulmonary embolism. All patients had optimal bronchodilator therapy. In total, 10 patients were ex-smokers and five were current smokers. Patients were also excluded if they were using cardiac drugs (angiotension-converting enzyme inhibitors, β-blockers, calcium channel blockers, nitrates or other vasodilators). As a control group, eight sex- and age-matched healthy subjects were included. The study was approved by the medical ethics committee of the VU University Medical Center (Amsterdam, the Netherlands) and written informed consent was obtained from all patients.
研究设计
在基线,进行正确的心脏导管插入术。为了评估西地那非对SV和运动能力,在MRI中,6分钟步行距离(6MWD)试验和心肺运动测试(CPET)的效果进行。该6MWD和CPET都在2个独立的天。对照组以同样的方式作为研究组接受了MRI检查。After the baseline measurements, 50 mg sildenafil was administered three times daily. Blood pressure was monitored for the first hours after sildenafil intake.
After 1 month, patients were phoned and all side-effects of sildenafil were recorded. After a treatment period of 3 months with sildenafil, the maximal workload was again determined during CPET and 6MWD. The SV response was assessed with MRI performed at the same workload as the initial measurement.
肺功能测试
标准肺活量测定,测定肺一氧化碳和RV和肺总容量的测量转移因子是根据欧洲呼吸协会/美国胸科学会(ATS)指南进行188bet官网地址13-15。The lung function test was repeated after 3 months in order to confirm the stability of the lung function over the study period and to assess possible effects of sildenafil on the lung function.
CPET
CPET是一种在医生监督下,标准化的,在电磁制动循环测力计(Lode, Groningen,荷兰)上逐渐增加工作速率以达到最大耐受的工作速率。负荷增加至运动自主中断,记录心电图及呼吸间呼吸气体交换(Vmax 229;感应医疗,约巴林达,加利福尼亚州,美国)。每分通气量(V”Ë)、摄氧量(V”Ø2),二氧化碳输出(V”CO2计算呼吸交换率。峰V”Ø2被定义为最高的V”Ø2症状限制运动的最后一分钟期间测量。通气效率通过增加在斜率计算评估V”Ë相对于CO2输出(V”Ë/V”CO2)。无氧阈(AT)是由V-斜率方法评价(即该V”Ø2在哪一级V”CO2开始增加)。通过1秒用力呼气量乘以37.5计算出通气储备。在最大运动测试中分析动脉血气。
6MWD试验
根据ATS指南进行了测试6MWD16。在6MWD试验后,立即获得博格呼吸困难分数。
右心脏导管插入术
右心导管插入术是在病人呼吸室内空气的情况下进行的。一种流动导向球囊导管(131HF7;Baxter Healthcare Corp., Irvine, CA, USA)被植入颈内静脉。记录了截止日期的测量值。心输出量采用直接Fick法测定。V”Ø2was measured for 5 min during catheterisation (Vmax 229; Sensormedics). Arterial and mixed venous blood gases were obtained from the radial and pulmonary arteries, respectively. Subsequently, patients inhaled NO for 5 min at a concentration of 20 ppm (flow rate 15 L·min-1)混合用室内空气(Nodomo;Drägers吕贝克,德国)。患者吸入并通过严格的面罩鼻腔呼出。最后,受试者被要求周期上横卧自行车(洛德)。如以前最大运动测试期间确定的工作速度提高到最大负荷的40%。达到血液动力学稳定状态后,反复血液动力学测量和血液采样。
运动诱发SV反应的MRI测量
磁共振图像和流量测量获得了1.5吨西门子索纳塔全身系统(西门子医疗解决方案,埃尔兰根,德国)如前所述17,with the exception that no breath-holds were used and temporal resolution was increased to 35 ms for flow quantification. SV was determined in both patients and controls by assessing the flow in the aorta. For the exercise measurements, the number of time phases in the cardiac cycle and the velocity sensitivity were adjusted to the increased cardiac frequency. The MRI exercise protocol consisted of a 3-min period of cycling in supine position on the same recumbent bicycle (Lode) used during invasive haemodynamic measurements after right heart catheterisation. Work rate was increased to 40% of maximal workload in the first minute as previously determined during maximal exercise testing. After 3 months, MRI was repeated at the same workload.
与MRI肺动脉压力变化的估计
为了测量西地那非对肺动脉压力的可能影响(PPA)加速时间/喷射时间比18和左室间隔弯曲(LVSB)19被测量。加速度时间是由主肺动脉开始前向血流到最大流速时刻的时间,用速度编码的cine MRI测量。左室矢状面是在早期舒张期开始时向左心室方向弯曲的小叶间隔的范围。这些测量在西地那非治疗3个月后重复进行。
统计分析
数据表示为平均值±SD。p值<0.05被认为是显著的。采用Wilcoxon配对秩检验比较SV和MRI的估计PPA休息和锻炼之间和基线测量和西地那非治疗之间。一曼 - 惠特尼U检验,使用了COPD患者和健康对照比较MRI测量。用于评价SV之间和右侧心脏导管插入术之前和西地那非处理后的SV响应之间的关系,使用MRI来确定,Pearson相关性分析。
结果
患者特征
Pulmonary function characteristics of the 15 COPD patients before and after treatment with sildenafil are reported in table 1⇓。在整个治疗期间,肺功能保持稳定。右心导管术中血流动力学测量结果见表2⇓。的意思是PPA(-PPA演习在所有患者中)和心输出量增加显著。九例患者被诊断为慢性阻塞性肺病相关的PH,其被定义为 -PPA≥25 mmHg with a pulmonary capillary wedge pressure <15 mmHg at rest, or a ―PPA≥30 mmHg during exercise20。Five patients showed PH at rest (33±7 mmHg). In all patients, PVR failed to decrease during submaximal exercise. Both arterial and mixed venous oxygen saturation decreased significantly during submaximal exercise. NO inhalation decreased ―PPA由14±8%,而心输出量和全身动脉压保持不变。
运动时SV响应与MRI测量
首先将右心导管插入术测量的SV与MRI测量的SV进行比较,发现两者具有良好的相关性(R2= 0.88;p<0.001)显示MRI测量SV的有效性。
Table 3⇓显示心脏MRI在休息和运动在基线和治疗过程后的结果。SV,心脏频率和心输出量从静止显著上升到锻炼。与COPD患者的比较,所述对照受试者表现出更高显著SV都在休息(62±12与运动时(70±15)与101±28 mL; p<0.05).
The SV did not change after 3 months of sildenafil treatment. Figure 1⇓shows the individual SV responses (SV during exercise minus SV at rest) of all patients before and after 3 months of treatment. As shown in figure 2⇓,治疗后SV反应与治疗前相似(R2 = 0.66; p<0.001). A subgroup analysis of the nine COPD patients with abnormally increased ―PPA显示较低的SV响应于锻炼与COPD患者具有正常压力(4.3±5.7对比与13。1±6.4 mL·beat-1),虽然这并没有达到显着性。In the COPD patients with associated PH, the SV response changed from 4.3±5.7 to 3.3±5.4 mL·beat-1(p = 0.2) after 3 months of treatment, which was not different from the non-PH group (13.1±6.4 to 13.2±6.7 mL·beat-1;p = 0.3).
Individual stroke volume (SV) response before and after 3 months of treatment with sildenafil. •: SV response, calculated as SV during exercise minus SV at rest; ○: mean SV response. Whiskers representSD。
![图2-](http://www.qdcxjkg.com/content/erj/31/4/759/F2.medium.gif)
Stroke volume response during exercise before and after 3 months of treatment with sildenafil. ○: chronic obstructive pulmonary disease (COPD) with pulmonary hypertension (PH) at rest; •: PH during submaximal exercise; ▪: COPD without PH. R2 = 0.66, p<0.001.
P的估计PA与MRI
The acceleration time/ejection time ratio and the LVSB did not change after treatment with sildenafil (0.32±0.02 to 0.32±0.03 and 0.31±0.13 to 0.31±0.15 cm, respectively).
CPET和6MWD试验
Table 4⇓给出治疗前后CPET参数及6MWD。在基线,56±28 W(37%),有一个峰值V”Ø2of 12.1±3.6 mL·kg-1·分-144 (±11%)。7名患者达到AT。血液pH值和CO2从休息到极限运动,紧张感并没有从7.42到7.37,从39±6到42±8毫米汞柱的变化。最大运动时通气储备为38±18%。15例患者中有5例达到运动通气峰值>70%。通气储备<15%被认为是限制通气运动的指标。在一个运动通气达到99%峰值的病人身上观察到这一点。最大运动能力和6分钟步行距离在西地那非治疗后无统计学差异。
副作用
据报道,服用西地那非后的副作用包括头痛(7例)、面部潮红(2例)和肌肉疼痛(2例)。所有患者均无明显不良反应,均完成研究。
讨论
本研究是在COPD第一亚极量运动和最大运动能力中,以评估对SV响应西地那非的影响。A 3个月的治疗期间没有改善SV或运动能力(通过6MWD试验和CPET评估)。此外,西地那非并没有改变动脉氧合在休息或最大运动时。
在休息时,SV在COPD患者明显降低与健康对照比较。这种差异运动时更为明显。在运动过程中出现了快速增加PPA即使在正常的患者静息压力。减小的SV响应的运动一起在与增加的结果PPA与以前的研究一致吗3,五,21这与运动中SV减少是由后负荷增加引起的观点相吻合。
的急剧增长有许多可能的原因PPA在慢性阻塞性肺病运动中。首先,由于肺血管的重构和毛细血管床的缩小,肺血管床的补充能力的丧失将导致肺血管的增加PPA如果心输出量增加。其次,运动还可能进一步增加肺泡血管的机械压迫,继发于肺泡血管的过度膨胀和内皮功能障碍,导致血管舒张剂NO的释放受损22。后者载体上的发现,即PPANO的吸入后下降,提供用于本研究的理由,因为是西地那非一个公认的替代刺激NO介导的血管舒张。
在本研究中,西地那非在3个月的治疗期间既没有改善SV,也没有增加运动能力。运动试验的所有参数保持不变。治疗反应的缺乏与ph的存在无关。虽然没有关于西地那非对慢性阻塞性肺病肺血流动力学长期影响的临床数据存在,但已经研究了低氧条件下西地那非的影响23-25。Faoro等。24显示,尽管西地那非改善峰V”Ø2在急性暴露于缺氧后健康受试者,它并没有影响峰V”Ø2nor maximal workload after 2 weeks of exposure to hypoxia, indicating that the effects of sildenafil under chronic and acute hypoxic conditions are different. In addition, Aldashev等。25在生活在高海拔地区的个体进行为期12周的西地那非治疗后,未发现心脏输出量或氧饱和度的改善;然而,与Farao的研究相反等。24由6MWD试验测得的运动能力得到改善。
几个因素可能解释在本研究中没有效果。首先,增加PPA可以只播放在受损的SV响应锻炼一个小角色。减少的静脉回流(由于内在的呼气末压力的增加),扰乱了左心室或右心室功能的固有减值舒张充盈可以是在COPD患者中更重要的决定因素26-28。
第二个可能的解释是,西地那非可能不会导致有效的减少的PPA在锻炼期间,慢性阻塞性肺病。这可以通过内膜纤维化的存在和肺泡血管继发于过度充气的机械压缩的影响来防止。
最后,SV降低和SV反应减弱可能反映这些患者严重的去污。尽管这种损伤的性质仍不清楚,但已观察到,在未分配的健康受试者中,静止SV降低,运动时SV反应受损29。
本研究中的一个限制是,少数患者具有在休息测量显著PH。However, these patients did not show a more favourable response than the non-PH patients, as presented in figure 2⇑。然而,不能排除有些COPD患者提供更先进的PH和更明显的血管内皮功能障碍可能来自西地那非治疗中获益。因此,一个大型试验需要确认在本研究中发现的结果。In addition, right heart catheterisation was not repeated after 3 months of treatment. However, based on the close relation between SV measured by right heart catheterisation and MRI at baseline, the present authors believe that MRI is a valid method to study SV in these patients.
结论
在15周慢性阻塞性肺疾病的患者的本研究中,已证实行程体积是在慢性阻塞性肺疾病的患者中减少与健康对照比较。However, 3 months of vasodilator therapy with sildenafil neither improved stroke volume nor exercise capacity. Although stroke volume was lower in the chronic obstructive pulmonary disease patients with associated pulmonary hypertension in comparison with the nonpulmonary hypertension patients, there was no difference in treatment response.
支持声明
H. J. Bogaard收到了来自荷兰心脏基金会助学金(荷兰Hartstichting批准号:2006022)。
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- 收到2007年8月31日。
- 公认2007年11月27日。
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